TY - JOUR
T1 - Immunohistochemical and Image Analysis-Based Study Shows That Several Immune Checkpoints are Co-expressed in Non–Small Cell Lung Carcinoma Tumors
AU - Parra, Edwin Roger
AU - Villalobos, Pamela
AU - Zhang, Jiexin
AU - Behrens, Carmen
AU - Mino, Barbara
AU - Swisher, Stephen
AU - Sepesi, Boris
AU - Weissferdt, Annika
AU - Kalhor, Neda
AU - Heymach, John Victor
AU - Moran, Cesar
AU - Zhang, Jianjun
AU - Lee, Jack
AU - Rodriguez-Canales, Jaime
AU - Gibbons, Don
AU - Wistuba, Ignacio I.
N1 - Publisher Copyright:
© 2018 International Association for the Study of Lung Cancer
PY - 2018/6
Y1 - 2018/6
N2 - Introduction: The understanding of immune checkpoint molecules’ co-expression in non–small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. Methods: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs — 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) — placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. Results: Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. Conclusions: We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.
AB - Introduction: The understanding of immune checkpoint molecules’ co-expression in non–small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. Methods: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs — 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) — placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. Results: Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. Conclusions: We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.
KW - Image analysis
KW - Immune checkpoints
KW - NCLC
KW - TMA
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UR - http://www.scopus.com/inward/citedby.url?scp=85047303845&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2018.03.002
DO - 10.1016/j.jtho.2018.03.002
M3 - Article
C2 - 29526824
AN - SCOPUS:85047303845
SN - 1556-0864
VL - 13
SP - 779
EP - 791
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 6
ER -